tbuckley/cabot-search huggingface dataset:
High-resolution daily profiles of tissue adrenal steroids by portable automated collection
Authors: Thomas J. Upton, Eder Zavala, Paal Methlie, Olle Kämpe, Stylianos Tsagarakis, Marianne Øksnes, Sophie Bensing, Dimitra A. Vassiliadi, Marianne A. Grytaas, Ileana R. Botusan, Grethe Ueland, Katarina Berinder, Katerina Simunkova, Maria Balomenaki, Dimitris Margaritopoulos, Nina Henne, Robin Crossley, Georgina Russell, Eystein S. Husebye, Stafford L. Lightman
Journal: Science Translational Medicine (2023)

Rhythms are intrinsic to endocrine systems, and disruption of these hormone oscillations occurs at very early stages of the disease. Because adrenal hormones are secreted with both circadian and ultradian periods, conventional single–time point measurements provide limited information about rhythmicity and, crucially, do not provide information during sleep, when many hormones fluctuate from nadir to peak concentrations. If blood sampling is attempted overnight, then this necessitates admission to a clinical research unit, can be stressful, and disturbs sleep. To overcome this problem and to measure free hormones within their target tissues, we used microdialysis, an ambulatory fraction collector, and liquid chromatography–tandem mass spectrometry to obtain high-resolution profiles of tissue adrenal steroids over 24 hours in 214 healthy volunteers. For validation, we compared tissue against plasma measurements in a further seven healthy volunteers. Sample collection from subcutaneous tissue was safe, well tolerated, and allowed most normal activities to continue. In addition to cortisol, we identified daily and ultradian variation in free cortisone, corticosterone, 18-hydroxycortisol, aldosterone, tetrahydrocortisol and allo-tetrahydrocortisol, and the presence of dehydroepiandrosterone sulfate. We used mathematical and computational methods to quantify the interindividual variability of hormones at different times of the day and develop “dynamic markers” of normality in healthy individuals stratified by sex, age, and body mass index. Our results provide insight into the dynamics of adrenal steroids in tissue in real-world settings and may serve as a normative reference for biomarkers of endocrine disorders (ULTRADIAN, NCT02934399).
<i>BLM</i> overexpression as a predictive biomarker for CHK1 inhibitor response in PARP inhibitor–resistant <i>BRCA</i> -mutant ovarian cancer
Authors: Nitasha Gupta, Tzu-Ting Huang, Jayakumar R. Nair, Daniel An, Grant Zurcher, Erika J. Lampert, Ann McCoy, Ashley Cimino-Mathews, Elizabeth M. Swisher, Marc R. Radke, Christina M. Lockwood, Jonathan B. Reichel, Chih-Yuan Chiang, Kelli M. Wilson, Ken Chih-Chien Cheng, Darryl Nousome, Jung-Min Lee
Journal: Science Translational Medicine (2023)

Poly(ADP-ribose) polymerase inhibitors (PARPis) have changed the treatment paradigm in breast cancer gene ( BRCA )–mutant high-grade serous ovarian carcinoma (HGSC). However, most patients eventually develop resistance to PARPis, highlighting an unmet need for improved therapeutic strategies. Using high-throughput drug screens, we identified ataxia telangiectasia and rad3-related protein/checkpoint kinase 1 (CHK1) pathway inhibitors as cytotoxic and further validated the activity of the CHK1 inhibitor (CHK1i) prexasertib in PARPi-sensitive and -resistant BRCA -mutant HGSC cells and xenograft mouse models. CHK1i monotherapy induced DNA damage, apoptosis, and tumor size reduction. We then conducted a phase 2 study (NCT02203513) of prexasertib in patients with BRCA -mutant HGSC. The treatment was well tolerated but yielded an objective response rate of 6% (1 of 17; one partial response) in patients with previous PARPi treatment. Exploratory biomarker analyses revealed that replication stress and fork stabilization were associated with clinical benefit to CHK1i. In particular, overexpression of Bloom syndrome RecQ helicase ( BLM ) and cyclin E1 ( CCNE1 ) overexpression or copy number gain/amplification were seen in patients who derived durable benefit from CHK1i. BRCA reversion mutation in previously PARPi-treated BRCA -mutant patients was not associated with resistance to CHK1i. Our findings suggest that replication fork–related genes should be further evaluated as biomarkers for CHK1i sensitivity in patients with BRCA -mutant HGSC.
An integrated isothermal nucleic acid amplification test to detect HPV16 and HPV18 DNA in resource-limited settings
Authors: Kathryn A. Kundrod, Maria Barra, Alexis Wilkinson, Chelsey A. Smith, Mary E. Natoli, Megan M. Chang, Jackson B. Coole, Akshaya Santhanaraj, Cesaltina Lorenzoni, Celda Mavume, Hira Atif, Jane Richards Montealegre, Michael E. Scheurer, Philip E. Castle, Kathleen M. Schmeler, Rebecca R. Richards-Kortum
Journal: Science Translational Medicine (2023)

High-risk human papillomavirus (HPV) DNA testing is widely acknowledged as the most sensitive cervical cancer screening method but has limited availability in resource-limited settings, where the burden of cervical cancer is highest. Recently, HPV DNA tests have been developed for use in resource-limited settings, but they remain too costly for widespread use and require instruments that are often limited to centralized laboratories. To help meet the global need for low-cost cervical cancer screening, we developed a prototype, sample-to-answer, point-of-care test for HPV16 and HPV18 DNA. Our test relies on isothermal DNA amplification and lateral flow detection, two technologies that reduce the need for complex instrumentation. We integrated all test components into a low-cost, manufacturable platform, and performance of the integrated test was evaluated with synthetic samples, provider-collected clinical samples in a high-resource setting in the United States, and self-collected clinical samples in a low-resource setting in Mozambique. We demonstrated a clinically relevant limit of detection of 1000 HPV16 or HPV18 DNA copies per test. The test requires six user steps, yields results in 45 min, and can be performed using a benchtop instrument and minicentrifuge by minimally trained personnel. The projected per-test cost is <$5, and the projected instrumentation cost is <$1000. These results show the feasibility of a sample-to-answer, point-of-care HPV DNA test. With the inclusion of other HPV types, this test has the potential to fill a critical gap for decentralized and globally accessible cervical cancer screening.
An adenoviral-vectored vaccine confers seroprotection against capsular group B meningococcal disease
Authors: Christina Dold, Leanne Marsay, Nelson Wang, Laura Silva-Reyes, Elizabeth Clutterbuck, Gavin K. Paterson, Kelsey Sharkey, David Wyllie, Peter T. Beernink, Adrian V. Hill, Andrew J. Pollard, Christine S. Rollier
Journal: Science Translational Medicine (2023)

Adenoviral-vectored vaccines are licensed for prevention of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and Ebola virus, but, for bacterial proteins, expression in a eukaryotic cell may affect the antigen’s localization and conformation or lead to unwanted glycosylation. Here, we investigated the potential use of an adenoviral-vectored vaccine platform for capsular group B meningococcus (MenB). Vector-based candidate vaccines expressing MenB antigen factor H binding protein (fHbp) were generated, and immunogenicity was assessed in mouse models, including the functional antibody response by serum bactericidal assay (SBA) using human complement. All adenovirus-based vaccine candidates induced high antigen-specific antibody and T cell responses. A single dose induced functional serum bactericidal responses with titers superior or equal to those induced by two doses of protein-based comparators, as well as longer persistence and a similar breadth. The fHbp transgene was further optimized for human use by incorporating a mutation abrogating binding to the human complement inhibitor factor H. The resulting vaccine candidate induced high and persistent SBA responses in transgenic mice expressing human factor H. The optimized transgene was inserted into the clinically relevant ChAdOx1 backbone, and this vaccine has now progressed to clinical development. The results of this preclinical vaccine development study underline the potential of vaccines based on genetic material to induce functional antibody responses against bacterial outer membrane proteins.
Impact of acute alcohol consumption on circulating microbiome in asymptomatic alcohol-related liver disease
Authors: Mads Israelsen, Camila Alvarez-Silva, Bjørn Stæhr Madsen, Camilla Dalby Hansen, Nikolaj Christian Torp, Stine Johansen, Johanne Kragh Hansen, Katrine Prier Lindvig, Jeanlouis Insonere, Virginie Riviere, Helene Bæk Juel, Asker Brejnrod, Lars Juhl Jensen, Maja Thiele, Benjamin Lelouvier, Torben Hansen, Manimozhiyan Arumugam, Aleksander Krag
Journal: Gut (2023)
Cytokine-directed cellular cross-talk imprints synovial pathotypes in rheumatoid arthritis
Authors: Maximilian Kugler, Mirjam Dellinger, Felix Kartnig, Lena Müller, Teresa Preglej, Leonhard X Heinz, Elisabeth Simader, Lisa Göschl, Stephan E Puchner, Sebastian Weiss, Lisa E Shaw, Matthias Farlik, Wolfgang Weninger, Giulio Superti-Furga, Josef S Smolen, Guenter Steiner, Daniel Aletaha, Hans P Kiener, Myles J Lewis, Costantino Pitzalis, Anela Tosevska, Thomas Karonitsch, Michael Bonelli
Journal: Annals of the Rheumatic Diseases (2023)

Structural reorganisation of the synovium with expansion of fibroblast-like synoviocytes (FLS) and influx of immune cells is a hallmark of rheumatoid arthritis (RA). Activated FLS are increasingly recognised as a critical component driving synovial tissue remodelling by interacting with immune cells resulting in distinct synovial pathotypes of RA.
Prostate cancer screening: well intentioned initiatives may use up resources but not improve health outcomes
Authors: Sonya H Bushell, David Spitzer, Phil Whittaker, Avril Nexus, Neal Maskrey, Maggie Helliway, Nick Price, Lindsey Pope, Clare Etherington, James Larcombe, Julie Grigg, Susan Bewley, David Taylor
Journal: BMJ (2023)
PD-L1/PD-1 checkpoint pathway regulates hippocampal neuronal excitability and learning and memory behavior
Authors: Junli Zhao, Sangsu Bang, Kenta Furutani, Aidan McGinnis, Changyu Jiang, Alexus Roberts, Christopher R. Donnelly, Qianru He, Michael L. James, Miles Berger, Mei-Chuan Ko, Haichen Wang, Richard D. Palmiter, Ru-Rong Ji
Journal: Neuron (2023)
Clinical Course of Patients in Cardiogenic Shock Stratified by Phenotype
Authors: Elric Zweck, Manreet Kanwar, Song Li, Shashank S Sinha, A Reshad Garan, Jaime Hernandez-Montfort, Yijing Zhang, Borui Li, Paulina Baca, Fatou Dieng, Neil M Harwani, Jacob Abraham, Gavin Hickey, Sandeep Nathan, Detlef Wencker, Shelley Hall, Andrew Schwartzman, Wissam Khalife, Claudius Mahr, Ju H Kim, Esther Vorovich, Evan H Whitehead, Vanessa Blumer, Ralf Westenfeld, Daniel Burkhoff, Navin K Kapur
Journal: JACC Heart Failure (2023)
Evaluating the use of fluorine-18 fluorodeoxyglucose positron emission tomography/computed tomography in the workup of Staphylococcus aureus bacteraemia: a cost-utility analysis
Authors: Sean W.X. Ong, Alice Zhabokritsky, Nick Daneman, Steven Y.C. Tong, Harindra C. Wijeysundera
Journal: Clinical Microbiology and Infection (2023)
Mannosylated glycans impair normal T-cell development by reprogramming commitment and repertoire diversity
Authors: Manuel M Vicente, Inês Alves, Ângela Fernandes, Ana M Dias, Beatriz Santos-Pereira, Elena Pérez-Anton, Sofia Santos, Tao Yang, Alexandra Correia, Anja Münster-Kühnel, Afonso R M Almeida, Sarina Ravens, Gabriel A Rabinovich, Manuel Vilanova, Ana E Sousa, Salomé S Pinho
Journal: Cellular and Molecular Immunology (2023)

Abstract T-cell development ensures the formation of diverse repertoires of T-cell receptors (TCRs) that recognize a variety of antigens. Glycosylation is a major posttranslational modification present in virtually all cells, including T-lymphocytes, that regulates activity/functions. Although these structures are known to be involved in TCR-selection in DP thymocytes, it is unclear how glycans regulate other thymic development processes and how they influence susceptibility to disease. Here, we discovered stage-specific glycome compositions during T-cell development in human and murine thymocytes, as well as dynamic alterations. After restricting the N -glycosylation profile of thymocytes to high-mannose structures, using specific glycoengineered mice ( Rag1 Cre Mgat1 fl/fl ), we showed remarkable defects in key developmental checkpoints, including ß-selection, regulatory T-cell generation and γδT-cell development, associated with increased susceptibility to colon and kidney inflammation and infection. We further demonstrated that a single N -glycan antenna (modeled in Rag1 Cre Mgat2 fl/fl mice) is the sine-qua-non condition to ensure normal development. In conclusion, we revealed that mannosylated thymocytes lead to a dysregulation in T-cell development that is associated with inflammation susceptibility.
Trends in the approval of cancer therapies by the FDA in the twenty-first century
Authors: Emma C Scott, Andrea C Baines, Yutao Gong, Rodney Moore, Gulsum E Pamuk, Haleh Saber, Ashim Subedee, Matthew D Thompson, Wenming Xiao, Richard Pazdur, V Ashutosh Rao, Julie Schneider, Julia A Beaver
Journal: Nature Reviews Drug Discovery (2023)
Saline at lower tonicity in cystic fibrosis (SALTI-CF) trial comparing 0.9%<i>versus</i>3%<i>versus</i>6% nebulised saline
Authors: Tiffany J. Dwyer, Mark R. Elkins, Ruth Dentice, Samantha Forbes, Peter Cooper, Adam Jaffe, Jennifer Bishop, Peter G. Middleton, Peter Wark, Peter T.P. Bye
Journal: European Respiratory Journal (2023)

In people with cystic fibrosis (CF), regular nebulisation of 6% or 7% saline improves lung function; however, these concentrations are not always tolerable. Clinically, some CF patients report using lower concentrations of saline to improve tolerability, yet the effects of lower concentrations are unknown. This study therefore aimed to evaluate the relative effectiveness and tolerability of 0.9%
Real-world comparative effectiveness of three single-inhaler dual bronchodilators for the treatment of COPD
Authors: Jiaying Li, Sophie Dell'Aniello, Pierre Ernst, Samy Suissa
Journal: European Respiratory Journal (2023)

Background Single-inhaler dual bronchodilators are now recommended as initial treatment of COPD for patients with multiple exacerbations or with moderate or severe dyspnoea. It is unclear whether there are differences in effectiveness among commonly used dual bronchodilators. Methods We identified a cohort of COPD patients, aged ≥40 years, treated during 2017–2020, from the UK Clinical Practice Research Datalink, a real-world practice setting. Inhaled corticosteroid-naïve patients initiating vilanterol–umeclidinium (VIL–UME) were compared with those initiating olodaterol–tiotropium (OLO–TIO) or indacaterol–glycopyrronium (IND–GLY) dual bronchodilators primarily on the incidence of moderate and severe COPD exacerbation over 1 year, and corresponding hazard ratios (HRs), after adjustment by propensity score weighting. Results The cohort included 15 224 initiators of VIL–UME, 5536 initiators of OLO–TIO and 5059 initiators of IND–GLY. The HR of a moderate or severe exacerbation with VIL–UME was 0.91 (95% CI 0.85–0.97) compared with OLO–TIO and 0.96 (95% CI 0.89–1.03) compared with IND–GLY. The risk of severe exacerbation was not different for VIL–UME when compared with OLO–TIO (HR 1.04, 95% CI 0.86–1.26) and IND–GLY (HR 1.05, 95% CI 0.86–1.28). All-cause mortality was lower with VIL–UME compared with IND–GLY (HR 0.82, 95% CI 0.68–0.98), but not compared with OLO–TIO (HR 0.87, 95% CI 0.72–1.04). Conclusion In a real-world setting of COPD treatment, the three dual bronchodilator combinations were similarly effective on the risk of a severe exacerbation of COPD. However, the VIL–UME and IND–GLY combinations may confer slightly superior effectiveness than OLO–TIO on the risk of moderate or severe exacerbation. The potential lower mortality with VIL–UME warrants further investigation.
Reply to Carlos Gustavo Trujillo, Sebastián Peña Rodríguez, and Cesar Díaz Ritter’s Letter to the Editor re: Jean-Nicolas Cornu, Paul Zantek, Glyn Burtt, et al. Minimally Invasive Treatments for Benign Prostatic Obstruction: A Systematic Review and Network Meta-analysis. Eur Urol 2023;83:534–47
Authors: Jean-Nicolas Cornu, Bilal Chughtai
Journal: European Urology (2023)
A Pilot Study on Hyperthermic Intraperitoneal Chemotherapy after Radical or Partial Cystectomy with Pelvic Lymph Node Dissection for High-risk Muscle-invasive Bladder Cancer
Authors: Leonardo D. Borregales, Siv Venkat, Lina Posada Calderon, Patrick Lewicki, Thomas Flynn, Bishoy M. Faltas, Ana M. Molina, David M. Golombos, Padraic O'Malley, Douglas S. Scherr
Journal: European Urology (2023)
Diet for the prevention and management of sarcopenia
Authors: Riccardo Calvani, Anna Picca, Hélio José Coelho-Júnior, Matteo Tosato, Emanuele Marzetti, Francesco Landi
Journal: Metabolism (2023)

Sarcopenia is a geriatric condition characterized by a progressive loss of skeletal muscle mass and strength, with an increased risk of adverse health outcomes (e.g., falls, disability, institutionalization, reduced quality of life, mortality). Pharmacological remedies are currently unavailable for preventing the development of sarcopenia, halting its progression, or impeding its negative health outcomes. The most effective strategies to contrast sarcopenia rely on the adoption of healthier lifestyle behaviors, including adherence to high-quality diets and regular physical activity. In this review, the role of nutrition in the prevention and management of sarcopenia is summarized. Special attention is given to current "blockbuster" dietary regimes and agents used to counteract age-related muscle wasting, together with their putative mechanisms of action. Issues related to the design and implementation of effective nutritional strategies are discussed, with a focus on unanswered questions on the most appropriate timing of nutritional interventions to preserve muscle health and function into old age. A brief description is also provided on new technologies that can facilitate the development and implementation of personalized nutrition plans to contrast sarcopenia.
Differences in carbon metabolic capacity fuel co-existence and plasmid transfer between Salmonella strains in the mouse gut
Authors: Ersin Gül, Andrew Abi Younes, Jemina Huuskonen, Cheickna Diawara, Bidong D. Nguyen, Luca Maurer, Erik Bakkeren, Wolf-Dietrich Hardt
Journal: Cell Host & Microbe (2023)

Antibiotic resistance plasmids can be disseminated between different Enterobacteriaceae in the gut. Here, we investigate how closely related Enterobacteriaceae populations with similar nutrient needs can co-bloom in the same gut and thereby facilitate plasmid transfer. Using different strains of Salmonella Typhimurium (S.Tm SL1344 and ATCC14028) and mouse models of Salmonellosis, we show that the bloom of one strain (i.e., recipient) from very low numbers in a gut pre-occupied by the other strain (i.e., donor) depends on strain-specific utilization of a distinct carbon source, galactitol or arabinose. Galactitol-dependent growth of the recipient S.Tm strain promotes plasmid transfer between non-isogenic strains and between E. coli and S.Tm. In mice stably colonized by a defined microbiota (OligoMM12), galactitol supplementation similarly facilitates co-existence of two S.Tm strains and promotes plasmid transfer. Our work reveals a metabolic strategy used by Enterobacteriaceae to expand in a pre-occupied gut and provides promising therapeutic targets for resistance plasmids spread.
Tryptophan depletion sensitizes the AHR pathway by increasing AHR expression and GCN2/LAT1-mediated kynurenine uptake, and potentiates induction of regulatory T lymphocytes
Authors: Marie Solvay, Pauline Holfelder, Simon Klaessens, Luc Pilotte, Vincent Stroobant, Juliette Lamy, Stefan Naulaerts, Quentin Spillier, Raphaël Frédérick, Etienne De Plaen, Christine Sers, Christiane A Opitz, Benoit J Van den Eynde, Jingjing Zhu
Journal: Journal for ImmunoTherapy of Cancer (2023)

Background Indoleamine 2,3-dioxygenase 1 (IDO1) and tryptophan-dioxygenase (TDO) are enzymes catabolizing the essential amino acid tryptophan into kynurenine. Expression of these enzymes is frequently observed in advanced-stage cancers and is associated with poor disease prognosis and immune suppression. Mechanistically, the respective roles of tryptophan shortage and kynurenine production in suppressing immunity remain unclear. Kynurenine was proposed as an endogenous ligand for the aryl hydrocarbon receptor (AHR), which can regulate inflammation and immunity. However, controversy remains regarding the role of AHR in IDO1/TDO-mediated immune suppression, as well as the involvement of kynurenine. In this study, we aimed to clarify the link between IDO1/TDO expression, AHR pathway activation and immune suppression. Methods AHR expression and activation was analyzed by RT-qPCR and western blot analysis in cells engineered to express IDO1/TDO, or cultured in medium mimicking tryptophan catabolism by IDO1/TDO. In vitro differentiation of naïve CD4 + T cells into regulatory T cells (Tregs) was compared in T cells isolated from mice bearing different Ahr alleles or a knockout of Ahr , and cultured in medium with or without tryptophan and kynurenine. Results We confirmed that IDO1/TDO expression activated AHR in HEK-293-E cells, as measured by the induction of AHR target genes. Unexpectedly, AHR was also overexpressed on IDO1/TDO expression. AHR overexpression did not depend on kynurenine but was triggered by tryptophan deprivation. Multiple human tumor cell lines overexpressed AHR on tryptophan deprivation. AHR overexpression was not dependent on general control non-derepressible 2 (GCN2), and strongly sensitized the AHR pathway. As a result, kynurenine and other tryptophan catabolites, which are weak AHR agonists in normal conditions, strongly induced AHR target genes in tryptophan-depleted conditions. Tryptophan depletion also increased kynurenine uptake by increasing SLC7A5 (LAT1) expression in a GCN2-dependent manner. Tryptophan deprivation potentiated Treg differentiation from naïve CD4 + T cells isolated from mice bearing an AHR allele of weak affinity similar to the human AHR. Conclusions Tryptophan deprivation sensitizes the AHR pathway by inducing AHR overexpression and increasing cellular kynurenine uptake. As a result, tryptophan catabolites such as kynurenine more potently activate AHR, and Treg differentiation is promoted. Our results propose a molecular explanation for the combined roles of tryptophan deprivation and kynurenine production in mediating IDO1/TDO-induced immune suppression.
Psychosocial interventions to improve the mental health of survivors of human trafficking: a realist review
Authors: Joelle Mak, Abigail Bentley, Sharli Paphitis, Mita Huq, Cathy Zimmerman, David Osrin, Delanjathan Devakumar, Melanie Abas, Ligia Kiss
Journal: The Lancet Psychiatry (2023)